Genetics researchers have identified 25 additional copy number variations (CNVs)—missing or duplicated stretches of DNA—that occur in some patients with autism. These CNVs, say the researchers, are “high impact”: although individually rare, each has a strong effect in raising an individual’s risk for autism.

“Many of these gene variants may serve as valuable predictive markers,” said the study’s corresponding author, Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia. “If so, they may become part of a clinical test that will help evaluate whether a child has an autism spectrum disorder.”

Hakonarson collaborated with scientists from the University of Utah and the biotechnology company Lineagen, Inc., in the study, published in the journal PLOS ONE.

The current study builds on and extends previous gene research by Hakonarson and other scientists on autism spectrum disorders (ASDs), a group of childhood neurodevelopmental disorders that cause impairments in verbal communication, social interaction and behavior. Estimated by the CDC to affect as many as one in 88 U.S. children, ASDs are known from family studies to be strongly influenced by genetics.

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A micrograph of a killer T cell, a white blood cell that destroys germs or cancers, but that can sometimes attack the body’s own normal cells.

Misguided killer T cells may be the missing link in sustained tissue damage in the brains and spines of people with multiple sclerosis, findings from the University of Washington reveal. Cytoxic T cells, also known as CD8+ T cells, are white blood cells that normally are in the body’s arsenal to fight disease.

Multiple sclerosis is characterized by inflamed lesions that damage the insulation surrounding nerve fibers and destroy the axons, electrical impulse conductors that look like long, branching projections. Affected nerves fail to transmit signals effectively.

Intriguingly, the UW study, published this week in Nature Immunology, also raises the possibility that misdirected killer T cells might at other times act protectively and not add to lesion formation. Instead they might retaliate against the cells that tried to make them mistake the wrappings around nerve endings as dangerous.

Scientists Qingyong Ji and Luca Castelli performed the research with Joan Goverman, UW professor and chair of immunology. Goverman is noted for her work on the cells involved in autoimmune disorders of the central nervous system and on laboratory models of multiple sclerosis.

Multiple sclerosis generally first appears between ages 20 to 40. It is believed to stem from corruption of the body’s normal defense against pathogens, so that it now attacks itself. For reasons not yet known, the immune system, which wards off cancer and infection, is provoked to vandalize the myelin sheath around nerve cells. The myelin sheath resembles the coating on an electrical wire. When it frays, nerve impulses are impaired.

Depending on which nerves are harmed, vision problems, an inability to walk, or other debilitating symptoms may arise. Sometimes the lesions heal partially or temporarily, leading to a see-saw of remissions and flare ups. In other cases, nerve damage is unrelenting.

The myelin sheaths on nerve cell projections are fashioned by support cells called oligodendrocytes. Newborn’s brains contain just a few sections with myelinated nerve cells. An adult’s brains cells are not fully myelinated until age 25 to 30.

For T cells to recognize proteins from a pathogen, a myelin sheath or any source, other cells must break the desired proteins into small pieces, called peptides, and then present the peptides in a specific molecular package to the T cells. Scientists had previously determined which cells present pieces of a myelin protein to a type of T cell involved in the pathology of multiple sclerosis called a CD4+ T cell. Before the current study, no cells had yet been found that present myelin protein to CD8+ T cells.

Scientists strongly suspect that CD8+ T cells, whose job is to kill other cells, play an important role in the myelin-damage of multiple sclerosis. In experimental autoimmune encephalitis, which is a mouse model of multiple sclerosis in humans, CD4+ T cells have a significant part in the inflammatory response. However, scientists observed that, in acute and chronic multiple sclerosis lesions, CD8+T cells actually outnumber CD4+ T cells and their numbers correlate with the extent of damage to nerve cell projections. Other studies suggest the opposite: that CD8+ T cells may tone down the myelin attack.

The differing observations pointed to a conflicting role for CD8+ T cells in exacerbating or ameliorating episodes of multiple sclerosis. Still, how CD8+ T cells actually contributed to regulating the autoimmune response in the central nervous system, for better or worse, was poorly understood.

TIP dendritic cells, stained to show their physical features.

Goverman and her team showed for the first time that naive CD8+ T cells were activated and turned into myelin-recognizing cells by special cells called Tip-dendritic cells. These cells are derived from a type of inflammatory white blood cell that accumulates in the brain and the spinal cord during experimental autoimmune encephalitis originally mediated by CD4+ T cells. The membrane folds and protrusions of mature dendritic cells often look like branched tentacles or cupped petals well-suited to probing the surroundings.

The researchers proposed that the Tip dendritic cells can not only engulf myelin debris or dead oligodendrocytes and then present myelin peptides to CD4+ T cells, they also have the unusual ability to load a myelin peptide onto a specific type of molecule that also presents it to CD8+ T cells. In this way, the Tip dendritic cells can spread the immune response from CD4+ T cells to CD8+ T cells. This presentation enables CD8+ T cells to recognize myelin protein segments from oligodendrocytes, the cells that form the myelin sheath. The phenomenon establishes a second-wave of autoimmune reactivity in which the CD8+ T cells respond to the presence of oligodendrocytes by splitting them open and spilling their contents.

“Our findings are consistent,” the researchers said, “with the critical role of dendritic cells in promoting inflammation in autoimmune diseases of the central nervous system.” They mentioned that mature dendritic cells might possibly wait in the blood vessels of normal brain tissue to activate T-cells that have infiltrated the blood/brain barrier.

The oligodendrocytes, under the inflammatory situation of experimental autoimmune encephalitis, also present peptides that elicit an immune response from CD8+ T cells. Under healthy conditions, oligodendrocytes wouldn’t do this.

The researchers proposed that myelin-specific CD8+ T cells might play a role in the ongoing destruction of nerve-cell endings in “slow burning” multiple sclerosis lesions. A drop in inflammation accompanied by an increased degeneration of axons (electrical impulse-conducting structures) coincides with multiple sclerosis leaving the relapsing-remitting stage of disease and entering a more progressive state.

Medical scientists are studying the roles of a variety of immune cells in multiple sclerosis in the hopes of discovering pathways that could be therapeutic targets to prevent or control the disease, or to find ways to harness the body’s own protective mechanisms. This could lead to highly specific treatments that might avoid the unpleasant or dangerous side effects of generalized immunosuppressants like corticosteroids or methotrexate.

(Source: washington.edu)

Researchers found information can be better retained with reinforcing stimuli delivered during sleep

When you’re studying for an exam, is there something you can do while you sleep to retain the information better?

"The question is, ‘What determines which information is going to be kept and which information is lost?’" says neuroscientist Ken Paller.

With support from the National Science Foundation (NSF), Paller and his team at Northwestern University are studying the connection between memory and sleep, and the possibilities of boosting memory storage while you snooze.

"We think many stages of sleep are important for memory. However, a lot of the evidence has shown that slow-wave sleep is particularly important for some types of memory," explains Paller.

Slow-wave sleep is often referred to as “deep sleep,” and consists of stages 3 and 4 of non-rapid-eye-movement sleep.

Paller’s lab group members demonstrated for Science Nation two of the tests they run on study participants. In the first experiment, the subjects learned two pieces of music in a format similar to the game Guitar Hero. During a short nap following learning, just one of the learned tunes was played softly several times, to selectively reinforce the memory for playing that tune without any reinforcement but not for the other tune. Paller wanted to know whether the test subjects could more accurately produce the tune played during sleep.

In the second exercise, the subjects were asked to memorize the location of 50 objects on a computer screen. The presentation of each object was coupled with a unique sound. During the post-learning nap, memory for the location of 25 objects was reinforced by the play-back of only 25 of the sounds. In this case, Paller wanted to know whether the subjects could remember object locations better if the associated sounds were played during sleep.

Researchers recorded electrical activity generated in the brain using EEG electrodes attached to the scalp. They thus determined whether the subjects entered “deep sleep,” and only those who did participated in the reinforcement experiments. In both experiments, participants did a better job remembering what was reinforced while they slept, compared to what was not reinforced.

"We think that memory processing happens during sleep every night," says Paller. "We’re at the beginning of finding out what types of memory can be reinforced, how large reinforcement effects can be, and what sorts of stimuli can be used to reactivate memories so that they can be better consolidated."

Paller’s goal is to better understand the fundamental brain mechanisms responsible for memory. And that, in turn, may help people with memory problems, including those who find themselves more forgetful as they age.

"We experience progressively less slow-wave sleep as we age. Of course, many brain mechanisms come into play to allow us to remember, including some processing that transpires during sleep. So, there’s a lot to figure out about how memory works, but I think it’s fair to say that the person you are when you’re awake is partly a function of what your brain does when you’re asleep," explains Paller. He says these reactivation techniques could turn out to be valuable for enhancing what people have learned.

"What is beautiful about this set of experiments is that Dr. Paller identified ‘deep sleep’ as a critical time window during which memory for specific experiences can be selectively enhanced by the method of reactivation without conscious effort," says Akaysha Tang, director of the cognitive neuroscience program in the NSF Directorate for Social, Behavioral and Economic Sciences.

"Normally, conscious rehearsal of memorized material is needed if one wants to remember something better or retain it for longer, and one has to find time to review or rehearse," continues Tang. "Dr. Paller and the members of his lab group showed that such selective enhancement could be achieved without conscious effort and without demanding more of one’s waking hours. So, instead of pulling that all-nighter to memorize the material, in the future, it may be possible to consolidate the memory by sleeping with a scientifically programmed lullaby!"

(Source: nsf.gov)